Enantioselective process

Abstract

The present invention relates to novel processes for the enantioselective iridium-catalysed hydrogenation of oximes and oxime ethers to provide compounds of formula (II) and salts thereof formula (I) and (II).

The invention claimed is: 
     
         1 . A process for hydrogenation of oximes of formula (I) in the presence of an iridium catalyst and an acid to produce a hydroxylamine of formula (II): 
       
         
           
           
               
               
           
         
         wherein the position labelled with the asterisk is an asymmetric center and one stereoisomer of hydroxylamine of formula (II) is produced in excess; 
         R 1  and R 2  are each independently C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 cyanoalkyl, C 1 -C 6 alkoxyC 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenyl, phenylC 1 -C 3 alkyl, phenylsulfonylC 1 -C 3 alkyl, C 1 -C 6 alkoxycarbonyl, a bridged carbocyclyl, heterocyclyl or heteroaryl, wherein the cycloalkyl, phenyl, heterocyclyl and heteroaryl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, phenyl, heteroaryl, C 1 -C 6 alkoxycarbonyl, acylamino, amido, cyano, nitro, azido, and C 2 -C 6 alkenyl; or a single group selected from pinacolborane, phenylsulfonyl, phenylC 1 -C 3 alkyl, or phenylC 1 -C 3 alkoxy; 
         R 3  is hydrogen, C 1 -C 8 alkyl, C 1 -C 8 hydroxyalkyl, C 1 -C 8 cyanoalkyl, C 1 -C 6 alkoxyC 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 2 -C 6 alkenyl, C 3 -C 8 cycloalkyl, phenylC 1 -C 3 alkyl, heterocyclylC 1 -C 3 alkyl or heterobicyclylC 1 -C 3 alkyl, wherein the cycloalkyl and heterocyclyl moieties are each optionally substituted with 1 to 5 groups selected from hydroxyl, halogen, C 1 -C 6 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, phenyl, heteroaryl, C 1 -C 6 alkoxycarbonyl, acylamino, amido, cyano, azido, nitro and C 2 -C 6 alkenyl; 
         and wherein R 1  and R 2  cannot be the same; or 
         R 1  and R 2  together with the carbon atom to which they are attached may form a 4- to 9-membered saturated or partially saturated asymmetric cycloalkyl or asymmetric heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S; or 
         R 1  and R 3  together with the carbon and oxygen atoms to which they are respectively attached, may form a 5- to 8-membered non-aromatic heterocyclyl ring, or an 8- to 10-membered partially saturated heterobicyclyl; 
         wherein the iridium catalysts of formula (IIIa) and (IIIb) are: 
       
       
         
           
           
               
               
           
         
         Wherein 
       
       
         
           
           
               
               
           
         
       
       represents an optionally substituted cyclopentadienyl ligand; 
       
         
           
           
               
               
           
         
       
       represents a bidentate chelating ligand comprising at least one carbon atom which coordinates to iridium and at least one nitrogen atom which coordinates to iridium;
 X represents an anionic group; 
 Y represents a neutral ligand; and 
 Z represents an anionic group. 
 
     
     
         2 . The process according to  claim 1 , wherein the iridium catalyst is of the formula (IIIa-1) or (IIIb-1) or the corresponding enantiomeric formula (IIIa-1-ent) or (IIIb-1-ent): 
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , and R 6  are each independently hydrogen or C 1 -C 3 alkyl;
 R 7  and R 8  are each independently hydrogen, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy. 
 
       
     
     
         3 . The process according to  claim 1 , wherein the iridium catalyst is of the formula (IIIa-2) or (IIIb-2) or the corresponding enantiomeric formula (IIIa-2-ent) or (IIIb-2-ent): 
       
         
           
           
               
               
           
         
         wherein R 4 , R 5 , and R 6  are each independently hydrogen or C 1 -C 3 alkyl;
 R 7  and R 8  are each independently hydrogen, hydroxyl, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 3 -C 8 cycloalkyl, phenyl, phenoxy, naphthyl, benzyl, or tert-butyldiphenylsilyloxy, wherein the aromatic ring of each phenyl, naphthyl, or benzyl moiety is optionally substituted with 1 to 5 groups selected from C 1 -C 6 alkyl, C 1 -C 6 haloalkyl and C 1 -C 6 alkoxy; 
 R 32  and R 33  are each independently hydrogen, halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy; 
 
         R 34  is halogen, C 1 -C 3 alkyl, or C 1 -C 3 alkoxy; or 
         R 32  and R 33 , or R 33  and R 34 , or R 32  and R 34  together with the carbon atoms to which they are attached may form a 5- to 10-membered carbocyclyl or heterocyclyl ring, wherein the heterocyclic moiety is a monocyclic ring which comprises 1, 2 or 3 heteroatoms, wherein the heteroatoms are individually selected from N, O and S. 
       
     
     
         4 . The process according to  claim 1 , wherein the bidentate chelating ligand is a ligand of structure (IVc): 
       
         
           
           
               
               
           
         
         wherein R 18 , R 19A , R 19B , R 20 , R 22 , R 23 , R 24  and R 25  are each independently hydrogen, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 haloalkyl, C 1 -C 8 haloalkoxy, or C 1 -C 8 alkoxycarbonyl, wherein each C 1 -C 8 alkoxy moiety is optionally substituted by 1 or 2 groups selected from hydroxy, C 1 -C 8 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 alkoxycarbonyl and phenyl; 
         R 21  is hydrogen, C 1 -C 8 alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C 1 -C 8 alkyl and C 1 -C 8 alkoxy; or 
         R 20  and R 21  together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S. 
       
     
     
         5 . The process according to  claim 1 , wherein the bidentate chelating ligand is a ligand of structure (IVe): 
       
         
           
           
               
               
           
         
         wherein, R 19A , R 19B , R 20 , R 23 , R 24  and R 15  are each independently hydrogen, C 1 -C 8 alkyl, or C 1 -C 8 alkoxy; 
         R 21  is hydrogen, C 1 -C 8 alkyl or phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C 1 -C 8 alkyl and C 1 -C 8 alkoxy; or 
         R 20  and R 21  together with the carbon atoms to which they are attached may form a 6- to 8-membered partially saturated cycloalkyl or heterocyclyl ring, wherein the heterocyclic moiety is a non-aromatic ring which comprises 1 or 2 heteroatoms, and wherein the heteroatoms are individually selected from N, O and S; 
         R 26  is a derivative of the following structure: 
       
       
         
           
           
               
               
           
         
         wherein R 27 , R 28 , R 29 , R 30 , and R 31  are each independently selected from hydrogen, C 1 -C 8 alkyl, C 3 -C 6 cycloalkyl, and phenyl, wherein each phenyl moiety is optionally substituted by 1 to 5 groups selected from C 1 -C 3 alkyl, halogen and C 1 -C 3 alkoxy, and wherein either, R 27  and R 28  may not be the same, or R 29  and R 30  may not be the same; or 
         R 29  and R 30  together with the carbon to which they are attached form and oxo (═O ) group. 
       
     
     
         6 . The process according to  claim 1 , wherein X represents an anionic group of the formula R 14 —SO 2 O— or R 15 —C(O)O—, wherein
 R 14  is halogen, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R 16 ; 
 R 16  is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, nitro, or halogen; 
 R 15  is C 1 -C 6 haloalkyl or phenyl, wherein the phenyl moieties are optionally substituted by 1, 2, 3 or 4 substituents, which may be the same or different, selected from R 17 ; and 
 R 17  is C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, nitro or halogen. 
 
     
     
         7 . The process according to  claim 1 , wherein Z is R 14 —SO 2 O − , mesylate, sulfate, hydrogensulfate, tetrafluoroborate, hexafluorophosphate, tetraphenylborate, or tetrakis(3,5-bis(trifluoromethyl)phenyl)borate. 
     
     
         8 . The process according to  claim 1 , wherein the acid is methanesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, sulfuric acid, trifluoroacetic acid or triflic acid. 
     
     
         9 . The process according to  claim 1 , wherein Y is H 2 O or MeCN. 
     
     
         10 . The process according to  claim 1 , wherein the oxime of formula (I) is N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-imine(I-1). 
     
     
         11 . The process according to  claim 1 , wherein the iridium catalyst is a compound of formula (III-1), (III-2), (III-3), (III-4), (III-15), (III-16), or (III-24): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         12 . The process according to  claim 1 , wherein the hydroxylamine of formula (II) is (2R)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1). 
     
     
         13 . The process according to  claim 12 , in which the (2R)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1) is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(1R)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide (XIII-1): 
       
         
           
           
               
               
           
         
       
     
     
         14 . The process according to  claim 1 , wherein the iridium catalyst is a compound of formula (III-1-ent), (III-2-ent), (III-3-ent), (III-4-ent), (III-15-ent), (III-16-ent), or (III-24-ent): 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The process according to  claim 1 , wherein the hydroxylamine of formula (II) is (2S)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1-ent). 
     
     
         16 . The process according to  claim 15 , in which the (2S)-N-methoxy-1-(2,4,6-trichlorophenyl)propan-2-amine (II-1-ent) is further reacted with 3-(difluoromethyl)-1-methyl-pyrazole-4-carbonyl chloride (XII) to provide 3-(difluoromethyl)-N-methoxy-1-methyl-N-[(1S)-1-methyl-2-(2,4,6-trichlorophenyl)ethyl]pyrazole-4-carboxamide (XIII-1-ent):